Aminothiolester compounds, pharmaceutical and cosmetic compositions containing same and uses thereof

ABSTRACT

The invention relates to novel aminothiol ester compounds having the general formula (I):  
                 
 
     and to a method for preparing them and to their use in pharmaceutical compositions intended for use in human or veterinary medicine (cancers and precancers, dermatological, rheumatic and ophthalmological complaints in particular) or in cosmetic compositions.  
     The invention also relates to a pharmaceutical or cosmetic composition, characterized in that it comprises, as active agent, a compound of general formula (I) in combination with a pharmaceutically or cosmetically acceptable support.

[0001] The present invention relates to aminothiol ester compounds offormula (I) and to their use as cell apoptosis inducers. The compoundsaccording to the invention have pronounced activity as apoptosisinducers and find applications more particularly in the topical andsystemic treatment of cancers and precancers and dermatological,rheumatic and ophthalmological complaints.

[0002] The present invention also relates to a pharmaceutical orcosmetic composition containing, as active agent, at least oneaminothiol ester compound of formula (I) in a physiologically acceptableexcipient.

[0003] The term “apoptosis” means the phenomenon of cell death asdescribed, inter alia, by Kerr J. F. R. et al., J. Cancer, 265, 239(1972). Apoptosis, which is a highly selective form of cell suicide, ischaracterized by readily observable morphological and biochemicalphenomena. Thus, a condensation of chromatin possibly associated with anendonuclease activity, the formation of apoptotic bodies and afragmentation of deoxyribonucleic acid (DNA), due to the activation ofendonucleases, into DNA fragments of 180-200 base pairs, giving aprofile which is readily recognizable by agarose gel electrophoresis,are thus observed.

[0004] Apoptosis is involved in tissue development, differentiation andrenewal. Inducing apoptosis is thus of major interest from a therapeuticviewpoint, and also from a cosmetic viewpoint.

[0005] A very large variety of natural or synthetic anticancer medicinalproducts currently available are apoptosis-inducing compounds.

[0006] Among these antineoplastic medicinal products, mention may bemade of alkylating agents such as cyclophosphamide, nitrosureas such as1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), intercalating agents suchas actinomycin D or adriamycin, purine or pyrimidine base analogues suchas 6-thioguanine and 5-fluorouracil, inhibitors of the de novo synthesisof purine bases, such as methotrexate, and finally tubulinpolymerization inhibitors such as Taxol®.

[0007] Moreover, it has already been proposed by the Applicant, inparticular in patent application WO 96/20701, to use anapoptosis-inducing compound chosen from methional, malonaldehyde and anyfactor for increasing the intracellular level of these compounds, thatis to say any compound having an action on the metabolism of methional,which is shown as a reminder in FIG. 1 (Quash et al., Biochem. J. 305,1017 (1995)).

[0008] 4-Methylthio-2-oxobutanoic acid (MTOB) transaminase inhibitors,composed of esters of L-methionine and of pyridoxal, have also beendisclosed in the said patent application, as factors for increasing theintracellular level of methional. As MTOB transaminase is an enzymeinvolved in the conversion of 4-methylthio-2-oxobutanoic acid tomethionine, the use of these compounds promotes the accumulation ofMTOB, a direct precursor of methional (FIG. 1) (Roch et al., Biochem. J.313, 973 (1996)).

[0009] One of the main drawbacks in using these substances is theabsence of selective apoptotic activity on tumour cells. Thus, itremains necessary to have available molecules which induce maximumapoptosis in tumour tissue while causing the least possible injury, andin a reversible manner, to the healthy tissues of the body.

[0010] In order to overcome this absence of selectivity, the Applicanthas disclosed, in patent application WO 98/44919, the use of aminothiolester derivatives, including thioampal, as inhibitors of the enzymealdehyde dehydrogenase (ALDH), an enzyme involved in the conversion ofmethional to methylpropionic acid, thus promoting the accumulation ofmethional. These compounds are selective inhibitors of the growth oftransformed cells that are apoptosis-resistant due to overexpression ofthe bcl₂ gene.

[0011] Such compounds are thus more specifically intended for treatingpathologies characterized by an overexpression of the bcl₂ gene, such asbreast cancer, B cell lymphoma, leukaemia, neuroblastoma, adenocarcinomaof the prostate, prolactinoma and other pituitary adenomas.

[0012] However, these aminothiol ester derivatives are difficult toprepare. Specifically, the processes for preparing them give a yield notexceeding 20%. Furthermore, these compounds have stability problems andmust be stored at temperatures of about −20° C. to prevent them fromdegrading.

[0013] It was thus desirable to develop novel compounds which are stableand easy to prepare in good yields and which selectively inhibit thegrowth of transformed cells that are apoptosis-resistant due tooverexpression of the bcl₂ gene.

[0014] This object of the present invention relates to novel aminothiolester compounds which may be represented by the general formula (I)below:

[0015] in which:

[0016] R₁ represents:

[0017] R₂ and R₃, independently, represent a saturated or unsaturated,cyclic, linear or branched alkyl radical containing from 1 to 7 carbonatoms or an aryl radical containing from 1 to 7 carbon atoms, or anaralkyl radical containing from 1 to 12 carbon atoms or, taken together,form a saturated alkyl ring containing from 3 to 7 carbon atoms,

[0018] R₄ represents a saturated or unsaturated, cyclic, linear orbranched alkyl radical containing from 1 to 7 carbon atoms or an arylradical containing from 1 to 7 carbon atoms or an aralkyl radicalcontaining from 1 to 12 carbon atoms,

[0019] R₅ and R₆, independently, represent a saturated or unsaturated,cyclic, linear or branched alkyl radical containing from 1 to 7 carbonatoms or an aryl radical containing from 1 to 7 carbon atoms, or anaralkyl radical containing from 1 to 12 carbon atoms or, taken together,form, with the nitrogen atom, a saturated or unsaturated nitrogenheterocycle containing from 2 to 6 carbon atoms, optionally substitutedwith an oxygen, a sulphur or with a nitrogen atom optionally substitutedwith a saturated or unsaturated, cyclic, linear or branched alkylradical containing from 1 to 7 carbon atoms or an aryl radicalcontaining from 1 to 7 carbon atoms or an aralkyl radical containingfrom 1 to 12 carbon atoms,

[0020] R₇ represents a hydrogen atom, a saturated or unsaturated,cyclic, linear or branched alkyl radical containing from 1 to 7 carbonatoms or an aryl radical containing from 1 to 7 carbon atoms or anaralkyl radical containing from 1 to 12 carbon atoms, and

[0021] X represents a halide ion or a nitrate, sulphate, sulphonate,carboxylate, thiocyanate or phosphate anion.

[0022] Among the cyclic alkyl radicals containing from 3 to 7 carbonatoms, mention may be made in particular of cyclopropyl, cyclopentyl,cyclohexyl and cycloheptyl radicals.

[0023] Among the saturated linear alkyl radicals containing from 1 to 7carbon atoms, mention may be made in particular of methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl or n-heptyl radicals.

[0024] Among the saturated and branched alkyl radicals containing from 1to 7 carbon atoms, mention may be made in particular of i-propyl,t-butyl, 2-butyl, 2-pentyl, i-pentyl, 2-hexyl, 3-hexyl, 2-heptyl,3-heptyl or i-heptyl radicals.

[0025] Among the unsaturated alkyl radicals containing from 1 to 7carbon atoms, mention may be made in particular of the allyl or vinylradical.

[0026] The expression “aralkyl radical containing from 1 to 12 carbonatoms” means a phenyl radical optionally substituted with linear orbranched alkyl radicals containing from 1 to 5 carbon atoms linked to asaturated linear alkyl chain containing from 1 to 5 carbon atoms, suchas the benzyl radical optionally substituted with an alkyl radicalcontaining from 1 to 5 carbon atoms, or 1-phenylethyl, 1-phenylpropyl,1-phenylbutyl or 1-phenylpentyl radicals.

[0027] Among the aryl radicals containing from 1 to 7 carbon atoms,mention may be made in particular of phenyl, tolyl, chlorophenyl,nitrophenyl, methoxyphenyl, thiophene and furan radicals. Among thenitrogen heterocycles, mention may be made in particular of pyrrolidine,piperidine, morpholine, thiamorpholine, piperazine, homopiperazine orN-methylpiperazine. Among the halides which may be mentioned are thefluorides, chlorides, bromides and, in particular, iodides.

[0028] Among the compounds of formula (I) falling within the context ofthe present invention, mention may be made in particular of thefollowing:

[0029] No. Compounds

[0030] 1- S-methyl 4-dimethylamino-4-methyl-2-pentynethioate

[0031] 2- S-methyl 4-methyl-4-trimethylammonium-2-pentynethioate iodide

[0032] 3- S-methyl 4-di-n-propylamino-4-methyl-2-pentynethioate

[0033] 4- S-methyl 4-methyl-4-pyrrodin-1-yl-2-pentynethioate

[0034] 5- S-methyl 4-methyl-4-morpholin-4-yl-2-pentynethioate

[0035] According to the present invention, the compounds of formula (I)that are more particularly preferred are those for which at least one ofthe conditions below is respected:

[0036] R₂ and R₃ represent a methyl radical;

[0037] R₄ represents a methyl radical;

[0038] R₅ and R₆, independently, represent an alkyl radical containingfrom 1 to 3 carbon atoms or, taken together, form, with the nitrogenatom, a nitrogen heterocycle chosen from pyrrolidine, piperidine andmorpholine;

[0039] R₇ represents a methyl radical or a hydrogen atom; and

[0040] X represents an iodide ion, a formate ion or a carboxylate ion.

[0041] A subject of the present invention is also processes forpreparing the compounds of formula (I).

[0042] The compounds of formula (I) (R₁=N(R₅R₆)) according to theinvention may be obtained according to the reaction scheme shown in FIG.2. The synthetic process consists in reacting butyllithium with apropargyl amine of formula (III) in THF. The intermediate lithiumacetylene formed is reacted with carbon oxysulphide (COS) and then withthe iodide R₄I. The thioester of formula (I) (R₁=N(R₅R₆)) is thusobtained in a yield of about 70%.

[0043] It may also be envisaged, as shown in FIG. 3, to react thelithium acetylene directly with a dialkyl or diaryl dithiocarbonate offormula (IV). These compounds are widely described, for example when R₄represents a methyl radical [Douglass, I. B., Warner, G. H., 78,6070-6071, (1956)].

[0044] The propargyl amines of formula (III) may be prepared accordingto the method of Hennion, G. F., Boiselle, A. P., J. Am. Chem. Soc., 26,725-727, (1961). As shown in FIG. 4, this method consists inchlorinating the tertiary alcohol of formula (V) in hydrochloric acidmedium in the presence of copper and cuprous chloride in a yield ofabout 70%.

[0045] The alcohol may be prepared, for example, from the ketone offormula R₂COR₃ and an acetylide

[0046] The propargyl chloride of formula (VI) is then subjected to theaction of the amine of formula R₅NHR₆ according to Hennion, G. F.,Nelson, K. W., J. Am. Chem. Soc., 79, 2142-2144, (1957) and Hennion, G.F., Hanzel, R. F., J. Am. Chem. Soc., 82, 4908-4912, (1960). The yieldsgenerally obtained are between 20% and 60%.

[0047] The compounds of formula (I) (R₁=N⁺ (R₅R₆R₇), X⁻) according tothe invention may be synthesized according to the reaction scheme ofFIG. 5. The synthetic process consists in reacting the halide R₇X(preferably the iodide) or the mineral or organic acid (R₇=H) with thecompound of formula (I) (R₁=N(R₅R₆)). The yields are about 70%.

[0048] Thus, whereas the synthesis of the compounds in patentapplication WO 98/44919 required a difficult step of deprotection of thepropargyl amine which prevented these compounds from being prepared on alarge scale, the synthesis of the compounds of the present invention hasthe advantage of being simpler and of being able to be developed on alarge scale, in better yields.

[0049] These novel compounds also have the advantageous of being morestable and, especially, much more active in inhibiting the growth oftransformed cells that are apoptosis-resistant due to overexpression ofthe bcl₂ gene than those disclosed in patent application WO 98/44919,such as thioampal.

[0050] The compounds according to the invention also have the advantageof being active in inhibiting the growth of transformed cells that areapoptosis-resistant not only due to overexpression of the bcl₂ gene, butalso due to the expression of the ALDH enzymes (ALDH1, ALDH2 and/orALDH3), overexpression of the MDR “Multi-Drug Resistant” gene or theBCL-X_(L) gene, which broadens their field of use.

[0051] Thus, the present invention also relates to the use of at leastone aminothiol ester derivative of formula (I) to prepare apharmaceutical composition for removing the inhibition of a nature forresistance to the induction of apoptosis in transformed cells, thisnature being due to the bcl₂ gene, the MDR gene or the BCL-X_(L) genepresent in these cells, or to the activity of ALDH.

[0052] The present invention also relates to the use of at least oneaminothiol ester derivative of formula (I) to prepare a pharmaceuticalcomposition for removing the inhibition of the chemotherapy-resistant orradiotherapy-resistant or the antiandrogen-resistant nature oftransformed cells.

[0053] More particularly, the chemotherapy-resistant orantiandrogen-resistant nature of transformed cells is due to the bcl₂gene, the BCL-X_(L), gene or the MDR gene present in these cells or tothe activity of the enzyme ALDH. More particularly, theradiotherapy-resistant nature of transformed cells is due to thepresence of the bcl₂ gene or to the high level of glutathione in thesecells.

[0054] Specifically, the aldehyde dehydrogenase (ALDH) enzymes catalysethe oxidation of various aliphatic and aromatic aldehydes to theircorresponding carboxylic acid in the presence of the cofactor NAD orNADP. These enzymes of different sub-families, and in particular ALDH1,ALDH2 or ALDH3, are present in various organs and play a role in thedetoxification of xenobiotics. Increasing the activity of these enzymescauses a resistance to anticancer agents such as cyclophosphamide [Magniet al., Blood, 87, 1097-1103, (1996)].

[0055] As indicated in patent application WO 98/44919, the use of aninhibitor of the activity of the ALDH1 enzyme makes it possible toremove the chemotherapy-resistant or antiandrogen-resistant natureinduced by ALDH1.

[0056] There are, within a cancer tumour, certain cancer cells known asmulti-drug resistant (MDR) cells which have a resistant nature tochemotherapeutic agents. Among these, the R7 cells which overexpress theMDR gene have been disclosed as being resistant to daunorubicin[Jeannesson, P. et al., Cancer Res., 50, 1231-1236, (1990)].

[0057] The LY-ar cell line, of mouse lymphoma cells, has been disclosedas being resistant to radiation, unlike the LY-as cells which aresensitive to radiotherapy [Mirkovic, N. et al., Oncogene, 15, 1461-1470,(1997)]. This resistance is due to an overexpression of the bcl₂ gene.

[0058] These compounds also have the advantage of inducing apoptosis ina large variety of transformed cells, thus allowing them to be used inthe preparation of pharmaceutical compositions for treating a largenumber of cancer pathologies, and also other diseases, more particularlydiseases associated with cell hyperproliferation, such as auto-immunediseases or allergies.

[0059] Although selectively inducing apoptosis in transformed cells,these compounds also show, in certain higher ranges of concentrations,apoptosis-inducing properties in normal cells, such as MRC5 cells. Thisallows them to be used in the preparation of cosmetic compositionsintended in particular for preventing or treating chronological orlight-induced ageing.

[0060] The subject-matter of the present invention also relates to thecompounds of formula (I) above as medicinal products. The compoundsaccording to the invention are particularly suitable in the followingfields of treatment:

[0061] 1) in the treatment or prevention of cancerous or precancerousconditions,

[0062] 2) for treating dermatological complaints associated with akeratinization disorder relating to differentiation and toproliferation, in particular for treating common acne, comedones,polymorphs, rosacea, nodulokystic acne, acne conglobata, senile acne andsecondary acne such as solar, medicinal or occupational acne,

[0063] 3) for treating ichthyosis, ichthyosiform conditions,palmoplantar keratoderma, leukoplakia and leukoplakiform conditions,

[0064] 4) for treating dermatological complaints with an inflammatoryimmuno-allergic component, with or without a cellular proliferationdisorder, and in particular all forms of psoriasis, whether cutaneous,mucous or ungual psoriasis, and even arthropathia psoriatica, oralternatively cutaneous atopy such as eczema, or, respiratory atopy orgingival hypertrophy,

[0065] 5) for treating dermal or epidermal proliferations, whetherbenign or malignant, whether or not of viral origin, such as commonwarts, flat warts and epidermodysplasia verruciformis, oral or floridpapillomatoses, T lymphoma and proliferations which may be induced byultraviolet light, in particular in the case of basal cell and pricklecell epithelioma, and also precancerous skin lesions such askeratoacanthomas,

[0066] 6) for treating immune dermatitides such as lupus erythematosus,bullous immune diseases and collagen diseases, such scleroderma,

[0067] 7) in the treatment of dermatological or systemic complaints withan immunological component,

[0068] 8) for-combating sebaceous function disorders such as thehyperseborrhea of acne or simple seborrhea,

[0069] 9) in the treatment of skin disorders due to exposure to UVradiation, and also for repairing or combating ageing of the skin,whether light-induced or chronological ageing, or for reducing actinickeratoses and pigmentations, or any pathology associated withchronological or actinic ageing,

[0070] 10) for preventing or treating cicatrization disorders or forpreventing or repairing stretch marks,

[0071] 11) in the treatment of inflammatory complaints such asarthritis,

[0072] 12) in the treatment of any cutaneous or systemic complaint ofviral origin, such as Kaposi's syndrome or hepatitis, and

[0073] 13) for treating certain ophthalmological disorders, inparticular corneopathy.

[0074] In the therapeutic fields mentioned above, the compoundsaccording to the invention may be advantageously used in combinationwith 3-methylthiopropanoyl thioester compounds of thioctic acid,methional, numerous antineoplastic agents, retinoids, withcorticosteroids or oestrogens, in combination with antioxidants, withα-hydroxy acids or α-ceto acids or derivatives thereof, withpotassium-channel blockers, in combination with other medicinal productsknown to interfere with the immune system (for example cyclosporin, FK506, glucocorticoids, monoclonal antibodies, cytokines or growthfactors), in combination with vitamin D derivatives or with vitamin Danalogue compounds.

[0075] Among the antineoplastic agents which may be mentioned inparticular are dexamethasone, cyclophosphamide, cisplatin, etoposide andBCNU (N,N-bis(2-chloroethyl)-N-nitrosourea), which are also capable ofinducing apoptosis.

[0076] Among the 3-methylthiopropanoyl thioesters of thioctic acid whichmay be mentioned in particular are the compounds disclosed in patentapplication EP 947 503 and more particularly compound 21, that is to say2′-(trimethylammonium)ethyl 6S,8S-bis(3-methylthiopropanoyl)octanoateiodide referred to hereinbelow as Metmetlico.

[0077] Specifically, a synergistic effect of the compounds of theinvention has been revealed in their antitumour activity when they areused in combination with an antitumour therapeutic agent as disclosed inpatent application EP 947 503.

[0078] The term “retinoid” means RAR or RXR receptor ligands, of naturalor synthetic, agonist or antagonist type.

[0079] Among the D vitamins or derivatives thereof which may bementioned in particular are vitamin D₂ and D₃ derivatives and inparticular 1,25-dihydroxy-vitamin D3, and compounds that are vitamin Danalogues chosen from the compounds disclosed in patent applications FR98/13747, FR 99/14783 or FR 99/14781.

[0080] Among the antioxidants which may be mentioned in particular areα-tocopherol, superoxide dismutase, ubiquinol and certainmetal-chelating agents.

[0081] Among the α-hydroxy acids or α-ceto acids or derivatives thereofwhich may be mentioned in particular are ketoleucine, ketoisoleucine,ketovaline, 2-oxobutyrate, 4-methylthio-2-oxobutanoic acid, lactic acid,malic acid, citric acid, glycolic acid, mandelic acid, tartaric acid andglyceric acid or salts, amides or esters thereof.

[0082] Among the potassium-channel blockers which may be mentioned inparticular are minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide)and its derivatives.

[0083] The Applicant has also found, surprisingly and unexpectedly,synergistic activity due to the combination of two compounds accordingto the invention.

[0084] A subject of the present invention is also novel pharmaceuticalor cosmetic compositions containing, as active principle, an effectiveamount of at least one novel compound which is the subject of theinvention, in a physiologically acceptable excipient.

[0085] A subject of the present invention is thus also such apharmaceutical composition intended in particular for treating theabovementioned complaints.

[0086] The present invention also relates to novel pharmaceuticalcompositions for the treatment, regression and prevention of cancer,containing, as antitumour therapeutic agent, an effective amount of atleast one novel compound which is the subject of the present invention,alone or in combination with an antitumour therapeutic agent chosen fromthose disclosed in patent application EP 947 503.

[0087] The compounds according to the invention may be administeredenterally, parenterally, topically or ocularly.

[0088] Via the enteral route, the pharmaceutical compositions may be inthe form of tablets, gel capsules, sugar-coated tablets, syrups,suspensions, solutions, powders, granules, emulsions, or lipid orpolymer vesicles or nanospheres or microspheres to allow controlledrelease.

[0089] Via the parenteral route, the composition may be in the form ofsolutions or suspensions for infusion or for injection.

[0090] The compounds of formula (I) according to the invention aregenerally administered at a daily dose of about 0.001 mg/kg to 100 mg/kgof bodyweight in 1 to 3 dosage intakes.

[0091] Via the topical route, the cosmetic or pharmaceutical compositionbased on compounds according to the invention is more particularlyintended for treating the skin of the scalp and mucous membranes and maybe in the form of ointments, creams, milks, pommades, powders,impregnated pads, solutions, gels, sprays, lotions or suspensions. Itmay also be in the form of lipid or polymer vesicles or nanospheres ormicrospheres or polymer patches or hydrogels to allow controlledrelease. As a variant, it may be in the form of a shampoo, a conditioneror a soap.

[0092] These topical-route compositions may be in anhydrous form, inaqueous form or in the form of an emulsion depending on the therapeuticindication.

[0093] Via the ocular route, they are mainly eye drops.

[0094] For a pharmaceutical application, the compounds of formula (I)are used topically or ocularly at a concentration generally of between0.0001% and 10% by weight and preferably between 0.001% and 1% by weightrelative to the total weight of the composition.

[0095] The compounds of formula (I) according to the invention also findan application in the cosmetic field, in particular in hair and bodyhygiene and especially for the treatment of skin with a tendency towardsacne, for the treatment or the prevention of stretch marks, inprotecting against harmful effects of sunlight, for preventing orcombating light-induced or chronological ageing, or for combating thegreasy appearance of the skin or the hair.

[0096] The concentration of compound of formula (I) in cosmeticcompositions may be between 0.001% and 3% by weight relative to thetotal weight of the composition.

[0097] The pharmaceutical or cosmetic compositions according to theinvention may also contain inert or even pharmacodynamically orcosmetically active additives or combinations of these additives, and inparticular: wetting agents; depigmenting agents such as hydroquinone,azeleic acid, caffeic acid or kojic acid; emollients; moisturizers suchas glycerol, PEG-400, thiamorpholine and its derivatives or urea;antiseborrhic or anti-acne agents, such as, S-carboxymethylcysteine,S-benzylcysteamine, their salts and their derivatives, or benzoylperoxide; antibiotics such as erythromycin and its esters, neomycin,clindamycin and its esters, and tetracyclines; antifungal agents such asketoconazole or poly(4,5-methylene-3-isothiazolinones); agents forpromoting hair regrowth, such as minoxidil(2,4-diamino-6-piperidino-pyrimidine 3-oxide) and its derivatives,diazoxide (7-chloro-3-methyl-1,2,4-benzo-thiadiazine 1,1-dioxide) andphenytoin (5,4-diphenyl-imidazoline-2,4-dione); non-steroidalanti-inflammatory agents; carotenoids and in particular β-carotene;anti-psoriatic agents such as anthralin and its derivatives, and,finally, eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoicacid, and their esters and amides.

[0098] The compositions according to the invention may also containflavour enhancers, preserving agents such as para-hydroxybenzoic acidesters, stabilizers, moisture regulators, pH regulators, osmoticpressure modifiers, emulsifiers or UV-A and UV-B screening agents.

[0099] Needless to say, a person skilled in the art will take care toselect the optional compound(s) to be added to these compositions suchthat the advantageous properties intrinsically associated with thepresent invention are not, or are not substantially, adversely affectedby the addition envisaged.

[0100] Several examples of the production of active compounds of formula(I) according to the invention and examples of tests to evaluate thebiological activity of the compounds of formula (I) according to theinvention will now be given by way of illustration and with no limitingnature.

A. EXAMPLES OF COMPOUNDS Example 1

[0101] Process for the Preparation of S-methyl4-dimethyl-amino-4-methyl-2-pentynethioate

[0102] 4.07 ml (9.24 mmol) of a 2.27 M solution of n-butyllithium inhexane is added over 5 minutes at −70° C. to a solution of 0.855 g of3-dimethylamino-3-methyl-1-butyne [Hennion, G. F., Nelson, K. W. (1957)J. Am. Chem. Soc., 79, 2142-2144]. After 5 minutes, the reaction mediumis warmed to 0° C. and stirred for a further 30 minutes at thistemperature. After cooling to −70° C., 2 ml of precondensed carbonoxysulphide are cannulated in and the mixture is stirred for 30 minutesat −70° C. The reaction medium is then maintained at 0° C. for 30minutes, followed by addition of 0.575 ml (9.24 mmol) of methyl iodideand stirring is continued for 2 hours at 0° C. The resulting mixture isdiluted in 250 ml of ether, washed with saturated sodium chloridesolution (3×30 ml) and dried over sodium sulphate. After evaporationunder vacuum and purification by chromatography on silica gel (elutingwith a 70/30 petroleum ethyl/ethyl acetate mixture), 1.16 g of thecompound of Example 1 are isolated in the form of a colourless oil(yield: 81%).

[0103]¹H NMR (300 MHz, CDCl₃): υ=1.42 (s, 6H, (CH₃)₂C), 2.31 (s, 6H,(CH₃)₂N), 2.39 (s, 3H, CH₃S).

Example 2

[0104] Process for the Preparation of S-methyl4-methyl-4-trimethylammonium-2-pentynethioate Iodide

[0105] 0.25 ml (4.02 mmol) of methyl iodide is added to 0.184 g (0.99mmol) of the compound obtained in Example 1 in 10 ml of ethyl acetate atroom temperature. The mixture is stirred for 4 days in the dark. Theresulting mixture is evaporated under vacuum and the residue is purifiedby chromatography on silica gel (eluting with a 90/10dichloromethane/methanol mixture). 0.229 g of the compound of Example 2(70% yield) is thus isolated in the form of a solid.

[0106]¹H NMR (300 MHz, CDCl₃): υ=1.96 (s, 6H, (CH₃)₂C), 2.46 (s, 3H,CH₃S), 3.62 (s, 6H, (CH₃)₃N).

Example 3

[0107] Process for the Preparation of S-methyl4-di-n-propylamino-4-methyl-2-pentynethioate

[0108] Preparation identical to that described in Example 1, using3-di-n-propylamino-3-methyl-1-butyne [Hennion, G. F., Hanzel, R. F., J.Am. Chem. Soc., 82, 4908-4912, (1960)] instead of3-dimethylamino-3-methyl-1-butyne. Scale: 2.8 mmol, purification bychromatography on silica gel (eluent: 95/5 petroleum ether/ethylacetate), yield: 75%. Colourless oil.

[0109]¹H NMR (300 MHz, CDCl₃): υ=0.86 (t, J=7.36, 6H, CH₃-CH₂) 1.46 (s,6H, (CH₃)₂C), 1.47 (m, 4H, CH₃-CH₂) 2.33 (s, 3H, CH₃S), 2.52 (m, 4H,CH₂N).

Example 4

[0110] Process for the Preparation of S-methyl4-methyl-4-pyrrodin-1-yl-2-pentynethioate

[0111] Preparation identical to that described in Example 1, using3-methyl-3-pyrrodin-1-yl-1-butyne [Hennion, G. F., Nelson, K. W., J. Am.Chem. Soc., 79, 2142-2144, (1957)] instead of3-dimethylamino-3-methyl-1-butyne. Scale: 2.8 mmol, purification bychromatography on silica gel (eluent: 70/30 petroleum ether/ethylacetate), yield: 85%. Colourless oil.

[0112]¹H NMR (300 MHz, CDCl₃): υ=1.45 (s, 6H, (CH₃)₂C), 1.81 (m, 4H,NCH₂-CH₂), 2.39 (s, 3H, CH₃S), 2.72 (m, 4H, CH₂N).

Example 5

[0113] Process for the Preparation of S-methyl4-methyl-4-morpholin-4-yl-2-pentynethioate

[0114] Preparation identical to that described in Example 1, using3-di-n-propylamino-3-methyl-1-butyne [Hennion, G. F., Hanzel, R. F., J.Am. Chem. Soc., 82, 4908-4912, (1960)] instead of3-methyl-3-morpholin-4-yl-1-butyne. Scale: 1.5 mmol, purification bychromatography on silica gel (eluent:60/40 petroleum ether/ethylacetate), yield: 77%. White solid.

[0115]¹H NMR (300 MHz, CDCl₃): υ=1.43 (s, 6H, (CH₃)₂C), 2.40 (s, 3H,CH₃S), 2.65 (m, 4H, CH₂O), 3.97 (m, 4H, CH₂N).

B. EXAMPLES OF TESTS TO EVALUATE THE BIOLOGICAL, ACTIVITY OF THECOMPOUNDS OF THE INVENTION Example 1 Effect of the Compounds on theGrowth of Transformed or Untransformed Cells

[0116] a) Effect of the Compounds on the Growth of DU145 and BAF3 bcl₂Cells

[0117] The cells used correspond to two cell lines: metastatic cells ofhuman prostate cancer (DU145) and murine lymphoid cells transfected withthe human bcl₂ gene (BAF3 bcl₂).

[0118] The procedure used for the tests on DU145 is as follows:

[0119] 10⁵ cells are incubated in the various wells of a microplate in 1ml of culture medium.

[0120] The compounds are added 4 hours after placing the cells in thewells.

[0121] After 72 hours, the cells are removed at different times. TheDU145 cells are washed twice with PBS and recovered directly with 0.1Msodium chloride.

[0122] The effect on the growth of the DU145 cells is measured byprotein assay according to the Lowry method (Lowry, O. H., Rosenbrough,N. J., Farr, A. L. and Randall, J. Biol. Chem. 193, 265-275, (1951)) andDNA assay by the Hoechst method (West, D. C., Sattar, A. and Kumar, S.,Anal. Biochem. 147, 289-295, (1985)).

[0123] The procedure used for the tests on BAF3 bcl₂ cells is asfollows:

[0124] 10⁵ cells are incubated in the various wells of a microplate in 1ml of culture medium. After incubation for 4 hours, the test compoundsare added to the wells containing the BAF3 bcl₂ cells.

[0125] For the BAF3 bcl₂ cells, the growth is measured by counting theviable cells in the presence of 0.1% Trypan blue. The control consistsof thioampal, disclosed in patent application WO 98/44919.

[0126] The results are collated in Table 1 below: TABLE I IC50 (μM) BAF3DU145 bcl₂ Comparative example Thioampal 650 100 Compounds of Example 15.9 0.25 the invention Example 3 8 2.7 Example 4 7.2 2.7 Example 5 8.812.0

[0127] The IC₅₀ concentration is the concentration corresponding to a50% inhibition of cell growth.

[0128] These results show that the IC₅₀ values of the compounds of theinvention are very much lower than that obtained for thioampal. Thus,the inhibition of growth of the DU145 cells and of the BAF3 bcl₂ cellsobtained with the compounds according to the invention is greater thanthe inhibition obtained with thioampal.

[0129] This inhibition of the growth of DU145 cells and of BAF3 bcl₂cells is at least partly due to an increase in the phenomena ofapoptosis of these cells.

[0130] Thus, these results suggest that the compounds of the inventioninduce apoptosis in the DU145cells and in the BAF3 bcl₂ cells more thanthioampal.

[0131] b) Effect of the Compounds on the Growth of L1210, L1210T, B16and MRC5 Cells

[0132] The cells used correspond to various cell lines: human lungnormal embryonic fibroblasts (MRC5), mouse melanoma cells (B16), mouselymphocytic leukaemia cells (L1210).and L1210T cells obtained byinfecting L1210 cells with a retroviral vector bearing human ALDH1 cDNA.

[0133] The procedure used for the tests on the L1210 cells is asfollows:

[0134] 10⁵ cells are incubated in the various wells of a microplate in 1ml of culture medium. After incubating for 4 hours, the test compoundsare added to the wells containing the L1210 cells.

[0135] For the L1210 cells, the growth is measured by counting theviable cells in the presence of 0.1% Trypan blue.

[0136] The procedure used for the tests on the B16 and MRC5 cells is asfollows:

[0137] The test compounds are added 4 hours after placing the cells inthe wells. After 72 hours, the cells are removed at different times. TheB16 and MRC5 cells are washed twice with PBS and recovered directly with0.1M sodium chloride.

[0138] The effect on the growth of the B16 and MRC5 cells is measured byprotein assay according to the Lowry method (Lowry, O. H., Rosenbrough,N. J., Farr, A. L. and Randall, J. Biol. Chem. 193, 265-275, (1951)) andDNA assay by the Hoechst method (West, D. C., Sattar, A. and Kumar, S.,Anal. Biochem. 147, 289-295, (1985)).

[0139] The results are collated in Table II below: TABLE II IC50 (μM)L1210 L1210T B16 MRC5 Comparative example Thioampal 90 140 NT >600Compound of the Example 1 1.2 1.6 0.8 8.4 invention

[0140] NT means not tested

[0141] The IC₅₀ concentration is the concentration corresponding to a50% inhibition of growth of the cells.

[0142] These results show that the IC₅₀ values of the compounds of theinvention are very low and very much lower than those obtained forthioampal. Thus, the inhibition of growth of the L1210, L1210T, B16 andMRC5, cells which is obtained with the compounds according to theinvention is significant and is much stronger than the inhibitionobtained with thioampal.

[0143] This inhibition of growth of the L1210, L1210T, B16 and MRC5cells is at least partly due to an increase in the phenomena ofapoptosis of these cells. Thus, these results suggest that the compoundsof the invention induce apoptosis in the L1210, L1210T, B16 and MRC5cells more than thioampal.

[0144] 2—Measurement of Apoptosis Induction in BAF3-b0 and BAF3-bcl₂Cells With the Compounds of the Invention

[0145] The BAF3-bcl₂ cells correspond to BAF3 cells (mouse lymphocytecells) tranfected with the bcl₂ gene. Among these cells, four linesknown as H16, G18, B14 and G21 overexpress the bcl₂ gene.

[0146] Hereinbelow, thee cells known as BAF3-b0 correspond to BAF3 cellsnot transfected with the bcl₂ gene.

[0147] Whereas the BAF3-b0 cells undergo apoptosis (more than 80% of thecells) in the absence of interleukin 3 (IL3) in 16 hours [according toCollins, M. K. L., Marvel, J., Malde, P. & Lopez-Rivas, A., J. Exp. Med.176, 1043-1051, (1992)], the BAF3-bcl₂ cells show no sign of apoptosisin the absence of IL3. They are thus apoptosis-resistant.

[0148] The procedure which was used is as follows: The BAF3-b0 orBAF3-bcl₂ cells, cultured in the presence of IL3, were labelled by amethod adapted from that disclosed in Wright, S. et al., J. of Cell.Biochem. 48, 344-355, (1992).

[0149] 10⁵ cells/ml were incubated with 4.62 KBq.ml⁻¹ [³H]-thymidine for40 hours at 37° C. After two washes with culture medium, 2.5×10⁶ cellswere cultured in the presence of the test compound.

[0150] After incubating for 24 hours, these cells were recovered bycentrifugation at 400×g for 5 minutes and washed 3 times with PBSbuffer. The cells recovered in the pellet were lysed in 2 ml of 0.1%Triton X-100, 20 mM EDTA, 5 mM Tris pH 8 and centrifuged at 30 000×g at4° C. for 30 minutes.

[0151] The supernatants were recovered and the pellets dissolved in 0.3ml of 0.5N NaOH.

[0152] Aliquots of the culture medium (1 ml), of the supernatant (0.3ml) and of the dissolved pellet (0.1 ml) were assayed in a scintillationcounter.

[0153] The precentage of DNA fragments is calculated in the followingway:${\% \quad {of}\quad {DNA}\quad {fragments}} = \frac{{{dpm}\quad {of}\quad {the}\quad {culture}\quad {medium}} + {{dpm}\quad {of}\quad {the}\quad {supernatant}}}{\begin{matrix}{{{dpm}\quad {of}\quad {the}\quad {culture}\quad {medium}} +} \\{{{dpm}\quad {of}\quad {the}\quad {supernatant}} + {{dpm}\quad {of}\quad {the}\quad {dissolved}\quad {pellet}}}\end{matrix}}$

[0154] (dpm=disintegrations per minute)

[0155] The percentage of fragmentation of the DNA is a direct measure ofthe apoptosis which the cells have undergone.

[0156] The results obtained are given in Table III TABLE III bcl₂ ClonesExample 1 (μM) b0 G21 G18 B14 H16 % expression of 0 0 6.4 22.1 50.8 72bcl₂ in BAF3 cells DNA 1 5.0 0 0.6 0 2.9 fragmentation (%) 2 10.6 5.87.3 2.0 6.3 4 46.4 29.3 52.7 44.3 65.3 8 71.1 71.8 84.3 90.0 94.2

[0157] The BAF-3-b0 cells serve as controls. The apoptosis of thesecells is induced by adding the compound of Example 1, and thisphenomenon increases in a dose-dependent manner.

[0158] These results show that the presence of a compound according tothe invention makes it possible to remove the inhibition of apoptosisdue to the bcl₂ gene in the H16, G18, B14 and G21 cell lines whichoverexpress the bcl₂ gene.

[0159] The procedure for the test given in Table 4 below is identical tothe previous procedure except that the incubation time is 6 hoursinstead of 24 hours: TABLE IV % fragmentation of the DNA of the bcl₂ H16cells Concentration (μM) Thioampal Example 1 50 0 2.15 100 1.6 0 200 7.630.4 400 16.4 83.8 600 26.5 81.5

[0160] The apoptosis of these cells is induced much more strongly withthe compound of Example 1 than with thioampal, and in a dose-dependentmanner.

[0161] These results show that the presence of the compound according tothe invention makes it possible to remove the inhibition of apoptosisdue to the bcl₂ gene, and does so much more strongly than the compoundsof the prior art.

Example 2 Effect of the Compounds on the Activity of ALDH1

[0162] The procedure used is given below:

[0163] 260 mU of ALDH from baker's yeast are preincubated at 37 or 0° C.in a mixture of 1 mM EDTA, 100 mM KCl, in 60 mM of sodium phosphatebuffer pH 6 in a final volume of 200 μl.

[0164] To each tube containing the 200 μl of mixture, the test compoundis added to a concentration of 400 μM, with the exception of a controlseries which contains no test compound.

[0165] The incubation carried out at 0° C. or at 37° C. is stopped byadding 100 μg of BSA (bovine serum albumin) and acetone at −20° C. to afinal concentration of 80% in order to precipitate the protein s (ALDHand BSA). The tubes are left at −20° C. for 1 hour and then centrifugedat 10 000 rpm for 10 minutes and washed with 80% acetone.

[0166] The proteins precipitated are dissolved in 358 μl of water andadded immediately to the reaction complex consisting of 1 mM EDTA, 100 mKCl and 2.35 mM NAD in 60 mM of pH 8.5 sodium phosphate buffer.

[0167] The reaction is started by adding 2 mM of propanal and theoptical density (OD) is measured at 340 nm at T=0 and at T=5 10, 20 and30 minutes.

[0168] The activity of the enzyme is measured by the variation inoptical density Δ OD per minute (Quash G. et al., Enzymology andmolecular biology of carbonyl metabolism, Weiner et al. eds., KluwerAcademic/Plenum Publishers, New York, 97-106).

[0169] The results obtained are given in FIG. 6.

[0170] The percentage activity (A %) of the ALDH1 enzyme obtained atdifferent preincubation times with the compound of Example 1 at 0° C.(represented by ▪) or 37° C. (represented by a ▴) or alternativelywithout preincubation with the compound of Example 1 at 0° C.(represented by □) or at 37° C. (represented by Δ) is measured as afunction of the time t (expressed in minutes).

[0171] When the pre-incubation with the compound of Example 1 is carriedout at a temperature of 0° C., there is no effect of inhibition of thecompound of Example 1 on the activity of the enzyme. Specifically, thetwo curves obtained with or without pre-incubation with the compound ofExample 1 are superimposable. This is explained by the fact that at thistemperature, the compound of Example 1has not been able to bemetabolized by the ALDH1. Consequently, the formation of covalent bondsbetween the active principle formed after cleavage and the enzyme hasnot been able to be established.

[0172] On the other hand, when the pre-incubation with the compound ofExample 1 is carried out at a temperature of 37° C., the enzyme ALDH1metabolizes the compound of Example 1 and bonds to it via covalentbonds, and an effect of inhibition of the activity of the enzyme isobserved. This effect increases as a function of the pre-incubation timewith the compound of Example 1.

[0173] These results show that the compounds according to the inventionmake it possible to reduce the activity of ALDH, and have the advantageof being of “suicide” type (irreversible covalent bonding with theenzyme ALDH), thus making it possible to remove the resistance toanticancer agents.

Example 3 Effect of the Compounds on R7 Cells Which Overexpress the MDRGene

[0174] The K562 cells used in this test do not overexpress the MDR geneand serve as control, and are human myeloid leukaemia cells, in contrastwith the R7 cells, cancer cells which overexpress the MDR gene.

[0175] The object of the present test is to demonstrate the effect ofthe compounds of the invention on these R7 cells.

[0176] The procedure used is given below:

[0177] 10⁵ cells were incubated in the various wells of a microplate in1 ml of culture medium. These are R7 cells, on the one hand, and K562cells, on the other hand.

[0178] After incubating for 4 hours, the test compound (compound ofExample 1 according to the invention, on the one hand, and daunorubicin,on the other hand) was added to the wells containing the cells.

[0179] After 72 hours, the cells were collected at different times.

[0180] The growth of the cells was measured by counting the viable cellsin the presence of 0.1% Trypan blue.

[0181] The results are given in FIGS. 7 and 8.

[0182]FIGS. 7 and 8 respectively represent the percentage inhibition (I%) by daunorubicin and the compound of Example 1 on the growth of the R7and K562 cells, obtained at increasing concentrations C. The resultsobtained with the K562 cells are symbolized by ♦ and those obtained withthe R7 cells are symbolized by ▴.

[0183] These results show that daunorubicin has no inhibitory effect onthe growth of the R7 cells overexpressing the MDR gene at concentrationsat which it inhibits the growth of the K562 cells.

[0184] On the other hand, the compound of Example 1 very stronglyinhibits the growth of the R7 cells. The inhibitory effect on the growthof the R7 cells is even greater than the inhibitory effect obtained atthe same concentrations on the growth of the K562 cells.

[0185] These results show that the compounds according to the inventionmake it possible to remove the chemotherapy resistance due to the MDRgene.

Example 4 Effect of the Combination of a Compound According to theInvention and of a Compound Chosen From Those Disclosed in PatentApplication EP 947 503 on the Growth of DU145 Cells

[0186] Patent application EP 947 503 discloses that methionalderivatives comprising the methional coupled via a thioester bond tothioctic acid show strong selective apoptotic activity towardstransformed cells and tumour cells. Among these compounds, mention maybe made of 2′-(trimethylammonium)ethyl6S,8S-bis(3-methylthiopropanoyl)octanoate iodide (compound 21 of thisdocument) referred to as metmetlico.

[0187] The procedure used is given below:

[0188] The cells used correspond to metastatic cells of human prostatecancer DU145.

[0189] 10⁵ DU145 cells are incubated in the various wells of amicroplate in 1 ml of culture medium.

[0190] The test compounds are added 4 hours after placing the cells inthe wells. After 72 hours, the cells are removed at different times. Thecells are washed twice with PBS and recovered directly with 0.1M sodiumchloride.

[0191] The effect on the growth of DU145 cells is measured by proteinassay according to the Lowry method (Lowry, O. H., Rosenbrough, N. J.,Farr, A. L. and Randall, J. Biol. Chem. 193, 265-275, (1951)) and DNAassay by the Hoechst method (West, D. C., Sattar, A. and Kumar, S.,Anal. Biochem. 147, 289-295, (1985)).

[0192] The test compounds are the compound of Example 1, metmetlico anda mixture thereof.

[0193] The results are collated in Table V: TABLE V % Inhibition ofgrowth Compound (concentration) of the DU145 cells Example 1 (2 μM) 5.8Example 1 (3 μM) 16.1 Example 1 (4 μM) 22.4 Metmetlico (25 μM) 0Metmetlico (50 μM) 0 Example 1 (2 μM) + Metmetlico (25 μM) 14.7 Example1 (2 μM) + Metmetlico (50 μM) 20.7 Example 1 (3 μM) + Metmetlico (25 μM)26.9 Example 1 (3 μM) + Metmetlico (50 μM) 36.9 Example 1 (4 μM) +Metmetlico (25 μM) 44.4 Example 1 (4 μM) + Metmetlico (50 μM) 41.3

[0194] The results show that the compound of Example 1 alone inhibitsthe growth of the DU145 cells. On the other hand, Metmetlico alone hasno inhibitory effect on the growth of these DU145 cells at theconcentrations used in this example.

[0195] The combination of a compound according to the invention and of acompound disclosed in patent application EP 947 503 synergisticallyinhibits the growth of the DU145 cells. These results demonstrate thepossibility of using these compounds in combination at doses that arevery much lower than those which may be used when they are used alone.

Example 5 Effect of the Combination of Two Compounds According to theInvention on the Growth of DU145 Cells or Normal Cells

[0196] 10⁵ normal human prostate cells or 10⁵ cancerous human prostatecells (DU145) are incubated in various wells of a microplate in 1 ml ofculture medium.

[0197] The compounds are added 4 hours after placing the cells in thewells.

[0198] After 72 hours, the cells are removed at different times. TheDU145 cells or the normal cells are washed twice with PBS and recovereddirectly with 0.1M sodium chloride.

[0199] The effect on the growth of the DU145 cells or the normal cellsis measured by protein assay according to the Lowry method (Lowry, O.H., Rosenbrough, N. J., Farr, A. L. and Randall, J. Biol. Chem. 193,265-275, (1951)) and DNA assay by the Hoechst method (West, D. C.,Sattar, A. and Kumar, S., Anal. Biochem. 147, 289-295, (1985)). TABLE VI% Inhibition of % Inhibition Test product normal human of DU145(concentration) prostate cells cells Example 1 (2 μM) 3.7 21.3 Example 5(2 μM) 1.3 25.2 Example 5 (1 μM) 0 14.3 Example 1 (2 μM) + Example 5 (2μM) 6.1 67.7 Example 1 (2 μM) + Example 5 (1 μM) 2.8 53.8

[0200] The combination of two compounds according to the inventionsynergistically inhibits the growth of the cancer cells without anyappreciable effect on the growth of the normal cells, thus making itpossible to further increase the activity and selectivity of thecompounds according to the invention with respect to transformed cells.These results demonstrate the possibility of using these compounds incombination at doses that are lower than those which may be used whenthe compounds are used alone.

C. FORMULATION EXAMPLES

[0201] 1) ORAL ROUTE (a) The composition below is prepared in the formof a 0.2 g tablet Compound of Example 1 0.005 g Pregelatinized starch0.065 g Microcrystalline cellulose 0.075 g Lactose 0.050 g Magnesiumstearate 0.005 g (b) A drinkable suspension, intended to be packaged in5 ml ampules, is prepared Compound of Example 2 0.001 g Glycerol 0.500 g70% Sorbitol 0.500 g Sodium saccharinate 0.010 g Methylpara-hydroxybenzoate 0.040 g Flavouring qs Purified water qs 5 ml (c)The formulation below intended to be packaged in gel capsules isprepared: Compound of Example 1 0.01 mg Compound of Example 5 0.01 mgCyclosporin 0.050 g Corn starch 0.060 g Lactose qs 0.300 g 2) TOPICALROUTE (a) The nonionic water-in-oil cream below is prepared: Compound ofExample 1 0.100 g Mixture of emulsifying lanolin alchols, 39.900 g waxesand refined oils, sold by the company BDF under the name “anhydrouseucerin” Methyl para-hydxoxybenzoate 0.075 g Propyl para-hydroxybenzoate0.075 g Sterile demineralized water qs 100.000 g (b) A gel is preparedby producing the following formulation: Compound of Example 1 0.001 gBase erythromycin 4.000 g Butyl hydroxytoluene 0.050 gHydroxypropylcelluluse sold by the 2.000 g company Hercules under thename “Klucel HF” Ethanol (at 95°) qs 100.000 g (c) A lotion is preparedby mixing together the following ingredients: Compound of Example 20.030 g Propylene glycol 5.000 g Butyl hydroxytoluene 0.100 g Ethanol(at 95°) qs 100.000 g (d) A cosmetic composition to combat the harmfuleffects of sunlight is prepared by mixing together the followingingredients: Compound of Example 1 1.00 g Benzylidenecamphor 4.00 gFatty acid triglycerides 31.00 g Glyceryl monostearate 6.00 g Stearicacid 2.00 g Cetyl alcohol 1.20 g Lanolin 4.00 g Preserving agents 0.30 gPropylene glycol 2.00 g Triethanolamine 0.50 g Fragrance 0.40 gDemineralized water qs 100.00 g (e) The nonionic oil-in-water creambelow is prepared: Compound of Example 3 0.500 g Retinoic acid 0.020 gCetyl alcohol 4.000 g Glyceryl monostearate 2.500 g PEG-50 stearate2.500 g Karite butter 9.200 g Propylene glycol 2.000 g Methylpara-hydroxybenzoate 0.075 g Propyl para-hydroxybenzoate 0.075 g Steriledemineralized water qs 100.000 g (f) A topical gel is prepared by mixingtogether the following ingredients: Compound of Example 4 0.050 gEthanol 43.000 g Tocopherol 0.050 g Carboxyvinyl polymer sold under the0.500 g name “Carbopol 941” by the company “Goodrich” Triethanolamine asan aqueous solution 3.800 g at 20% by weight Water 9.300 g Propyleneglycol qs 100.000 g (g) An oil-in-water cream is prepared by producingthe following formulation: Compound of Example 4 0.020 g Betamethasone17-valerate 0.050 g S-carboxymethylcysteine 3.000 g Polyoxyethylenestearate (40 mol of 4.000 g ethylene oxide), sold under the name “Myrj52” by the company “Atlas” Sorbitan monolaurate, polyoxyethylenated1.800 g with 20 mol of ethylene oxide, sold under the name “Tween 20” bythe company “Atlas” Mixture of glyceryl monostearate and 4.200 gdistearate sold under the name “Geleol” by the company “Gattefosse”Propylene glycol 10.000 g Butyl hydroxyanisole 0.010 g Butylhydroxytoluene 0.020 g Cetostearyl alcohol 6.200 g Preserving agents qsPerhydrosqualene 18.000 g Mixture of caprylic/capric triglycerides 4.000g sold under the name “Miglyol 812” by the company “Dynamit Nobel”Triethanolamine (99% by weight) 2.500 g Water qs 100.000 g (h) Theoil-in-water type cream below is prepared: Lactic acid 5.000 g Compoundof Example 2 0.020 g Polyoxyethylene stearate (40 mol of 4.000 gethylene oxide) sold under the name “Myrj 52” by the company “Atlas”Sorbitan monolaurate, polyoxyethylenated 1.800 g with 20 mol of ethyleneoxide, sold under the name “Tween 20” by the company “Atlas” Mixture ofglyceryl monostearate and 4.200 g distearate sold under the name“Geleol” by the company “Gattefosse” Propylene glycol 10.000 g Butylhydroxyanisole 0.010 g Butyl hydroxytoluene 0.020 g Cetostearyl alcohol6.200 g Preserving agents qs Perhydrosqualene 18.000 g Mixture ofcaprylic/capric triglycerides 4.000 g sold under the name “Miglyol 812”by the company “Dynamit Nobel” Water qs 100.000 g (i) The anhyrousointment below is prepared: Compound of Example 1 5.00 g Liquidpetroleum jelly 50.00 g Butyl hydroxytoluene 0.05 g White petroleumjelly qs 100.00 g 3) INTRALESIONAL ROUTE (a) The composition below isprepared: Compound of Example 3 0.002 g Ethyl oleate qs 10 g (b) Thecomposition below is prepared: Compound of Example 1 0.05% Polyethyleneglycol 20% 0.9% NaCl solution qs 100 (c) The composition below isprepared: Compound of Example 3 2.5% Polyethylene glycol 400 20% 0.9%NaCl solution qs 100 4) INTRAVENOUS ROUTE (a) The injectable compositionbelow is prepared: Compound of Example 1 0.001% Metmetlico 0.01%Polyethylene glycol 400 20% 0.9% NaCl solution qs 100 (b) The injectablecomposition below is prepared: Compound of Example 2 0.01% Polyethyleneglycol 400 20% 0.9% NaCl solution qs 100 (c) The cyclodextrincomposition below is prepared: Compound of Example 3 0.1 mg Cyclodextrin0.10 g Water for injection qs 10.00 g (d) The cyclodextrin compositionbelow is prepared: Compound of Example 4 0.01 g2-Hydroxypropylcyclodextrin 0.10 g Water for injection qs 10.00 g

1. Compound, characterized in that it corresponds to the general formula(I) below:

in which: R₁ represents:

R₂ and R₃, independently, represent a saturated or unsaturated, cyclic,linear or branched alkyl radical containing from 1 to 7 carbon atoms oran aryl radical containing from 1 to 7 carbon atoms, or an aralkylradical containing from 1 to 12 carbon atoms or, taken together, form asaturated alkyl ring containing from 3 to 7 carbon atoms, R₄ representsa saturated or unsaturated, cyclic, linear or branched alkyl radicalcontaining from 1 to 7 carbon atoms or an aryl radical containing from 1to 7 carbon atoms or an aralkyl radical containing from 1 to 12 carbonatoms, R₅ and R₆, independently, represent a saturated or unsaturated,cyclic, linear or branched alkyl radical containing from 1 to 7 carbonatoms or an aryl radical containing from 1 to 7 carbon atoms, or anaralkyl radical containing from 1 to 12 carbon atoms or, taken together,form, with the nitrogen atom, a saturated or unsaturated nitrogenheterocycle containing from 2 to 6 carbon atoms, optionally substitutedwith an oxygen, a sulphur or with a nitrogen atom optionally substitutedwith a saturated or unsaturated, cyclic, linear or branched alkylradical containing from 1 to 7 carbon atoms or an aryl radicalcontaining from 1 to 7 carbon atoms or an aralkyl radical containingfrom 1 to 12 carbon atoms, R₇ represents a hydrogen atom, a saturated orunsaturated, cyclic, linear or branched alkyl radical containing from 1to 7 carbon atoms or an aryl radical containing from 1 to 7 carbon atomsor an aralkyl radical containing from 1 to 12 carbon atoms, and Xrepresents a halide ion or a nitrate, sulphate, sulphonate, carboxylate,thiocyanate or phosphate anion.
 2. Compound according to claim 1,characterized in that the cyclic alkyl radical containing from 1 to 7carbon atoms is chosen from the cyclopropyl, cyclopentyl, cyclohexyl orcycloheptyl radical.
 3. Compound according to either of the precedingclaims, characterized in that the linear or branched saturated alkylradical is chosen from the methyl, ethyl, n-propyl, i-propyl, n-butyl,2-butyl, t-butyl, n-pentyl, 2-pentyl, i-pentyl, n-hexyl, 2-hexyl,3-hexyl, n-heptyl, 2-heptyl, 3-heptyl or i-heptyl radical.
 4. Compoundaccording to any one of the preceding claims, characterized in that thearyl radical is chosen from the phenyl, tolyl, chlorophenyl,nitrophenyl, methoxyphenyl, thiophene or furan radical.
 5. Compoundaccording to any one of the preceding claims, characterized in that thenitrogen heterocycle radical is chosen from pyrrolidine, piperidine,morpholine, thiamorpholine, piperazine, homopiperazine andN-methylpiperazine.
 6. Compound according to any one of the precedingclaims, characterized in that the unsaturated alkyl radical containingfrom 1 to 7 carbon atoms is chosen from the allyl or vinyl radical. 7.Compound according to any one of the preceding claims, characterized inthat the aralkyl radical containing from 1 to 12 carbon atoms is chosenfrom the benzyl radical optionally substituted with an alkyl radicalcontaining from 1 to 5 carbon atoms, and 1-phenylethyl, 1-phenylpropyl,1-phenylbutyl and 1-phenylpentyl radicals.
 8. Compound according to anyone of the preceding claims, characterized in that the halide ion ischosen from the fluoride, chloride, bromide and iodide.
 9. Compoundaccording to claim 1, characterized in that it is chosen from: S-methyl4-dimethylamino-4-methyl-2-pentynethioate; S-methyl4-methyl-4-trimethylammonium-2- pentynethioate iodide; S-methyl4-di-n-propylamino-4-methyl-2-pentynethioate; S-methyl4-methyl-4-pyrrodin-1-yl-2-pentynethioate; S-methyl4-methyl-4-morpholin-4-yl-2-pentynethioate.
 10. Compound according toclaim 1, characterized in that it has at least one of the followingcharacteristics: R₂ and R₃ represent a methyl radical; R₄ represents amethyl radical; R₅ and R₆, independently, represent an alkyl radicalcontaining from one to three carbon atoms or, taken together, form, withthe nitrogen atom, a nitrogen heterocycle chosen from pyrrolidine,piperidine and morpholine; R₇ represents a methyl radical or a hydrogenatom; and X represents an iodide ion, a formate ion or a carboxylateion.
 11. Compound according to any one of claims 1 to 10, as medicinalproduct.
 12. Use of a compound according to any one of claims 1 to 10,for the manufacture of a medicinal product intended for the treatmentof: 1) cancerous or precancerous conditions, 2) dermatologicalcomplaints associated with a keratinization disorder relating todifferentiation and to proliferation, in particular common acne,comedones, polymorphs, rosacea, nodulokystic acne, acne conglobata,senile acne and secondary acne such as solar, medicinal or occupationalacne, and/or 3) ichthyosis, ichthyosiform conditions, palmoplantarkeratoderma, leukoplakia and leukoplakiform conditions, and/or 4)dermatological complaints with an inflammatory immuno-allergiccomponent, with or without a cellular proliferation disorder, and inparticular psoriasis, arthropathia psoriatica, eczema, respiratory atopyand gingival hypertrophy, and/or 5) dermal or epidermal proliferations,whether benign or malignant, whether or not of viral origin, such ascommon warts, flat warts and epidermodysplasia verruciformis, oral orflorid papillomatoses, T lymphoma and proliferations which may beinduced by ultraviolet light, in particular in the case of basal celland prickle cell epithelioma, and also precancerous skin lesions such askeratoacanthomas, and/or 6) immune dermatitides such as lupuserythematosus, bullous immune diseases and collagen diseases, such asscleroderma, and/or 7) dermatological or systemic complaints with animmunological component, and/or 8) sebaceous function disorders such asthe hyperseborrhea of acne or simple seborrhea, and/or, 9) skindisorders due to exposure to UV radiation, light-induced orchronological ageing of the skin, or pigmentations and actinickeratoses, or pathologies associated with chronological or actinicageing, and/or 10) cicatrization disorders or stretch marks, and/or 11)inflammatory complaints such as arthritis, and/or 12) cutaneous orsystemic complaints of viral origin, such as Kaposi's syndrome orhepatitis, and/or 13) ophthalmological disorders, in particularcorneopathies.
 13. Use of a compound according to any one of claims 1 to10, for the manufacture of a medicinal product intended for thetreatment of cancerous or precancerous conditions.
 14. Composition,characterized in that it comprises, in a physiologically acceptablesupport, at least one of the compounds according to any one of claims 1to
 10. 15. Composition according to claim 14, characterized in that itcontains the active compound in an amount which is effective to induceapoptosis in transformed cells in a human or animal individual. 16.Pharmaceutical composition according to claim 14, characterized in thatit contains the active compound in an amount which is effective toremove the inhibition of a nature for resistance to the induction ofapoptosis in transformed cells, this nature being due to the bcl₂ geneor to the MDR gene or to the BCL-X_(L) gene, or to the enzyme ALDHpresent in these cells.
 17. Composition according to any one of claims14 to 16, characterized in that the concentration of the compound(s) isbetween 0.0001% and 10% by weight relative to the total weight of thecomposition.
 18. Composition according to any one of claims 14 to 17,characterized in that it also comprises at least one compound chosenfrom 3-methylthiopropanoyl thioesters of thioctic acid.
 19. Compositionaccording to claim 18, characterized in that it comprises2′-(trimethylammonium)ethyl 6S,8S-bis(3-methylthiopropanoyl)octanoateiodide.
 20. Composition according to any one of claims 14 to 19,characterized in that it comprises at least S-methyl4-dimethylamino-4-methyl-2-pentynethioate and S-methyl4-methyl-4-morpholin-4-yl-2-pentynethioate.
 21. Use, for the preparationof a composition intended to induce apoptosis in transformed cells, ofat least one compound according to any one of claims 1 to
 10. 22. Use,for the preparation of a composition intended to remove the inhibitionof a nature for resistance to the induction of apoptosis in transformedcells, this nature being due to the bcl₂ gene or the MDR gene or to theBCL-X_(L) gene, or to the enzyme ALDH present in these cells, of atleast one compound according to any one of claims 1 to
 10. 23. Use, forthe preparation of a pharmaceutical composition intended to remove theinhibition of the chemotherapy-resistant, radiotherapy-resistant orantiandrogen-resistant nature of transformed cells, of at least onecompound according to any one of claims 1 to
 10. 24. Use according toclaim 23, characterized in that the chemotherapy-resistant,radiotherapy-resistant or antiandrogen-resistant nature of transformedcells is due to the bcl₂ gene present in these cells.
 25. Use accordingto claim 23, characterized in that the chemotherapy-resistant orantiandrogen-resistant nature of transformed cells is due to the MDRgene present in these cells.
 26. Use according to claim 23,characterized in that the chemotherapy-resistant orantiandrogen-resistant nature of transformed cells is due to theBCL-X_(L) gene present in these cells.
 27. Use according to claim 23,characterized in that the chemotherapy-resistant orantiandrogen-resistant nature of transformed cells is due to theactivity of the enzyme ALDH.
 28. Use of a compound according to any oneof claims 1 to 10, taken alone or as a mixture with a compound chosenfrom 3-methylthiopropanoyl thioesters of thioctic acid, for thepreparation of a pharmaceutical composition intended for the treatment,regression and/or prevention of cancer tumours.
 29. Use according toclaim 28, characterized in that the 3-methylthiopropanoyl thioester ofthioctic acid is 2′-(trimethylammonium) ethyl 6S,8S-bis(3-methylthiopropanoyl)octanoate iodide.
 30. Cosmetic treatmentprocess which consists in applying a composition according to any one ofclaims 14 to 20 to the skin or the scalp.
 31. Process according to claim30, characterized in that it is intended for cleansing the skin, andmore particularly skin with a tendency towards acne, or the scalp, fortreating or preventing stretch marks, for protecting against the harmfuleffects of sunlight, for preventing and/or combating light-induced orchronological ageing or for combating the greasy appearance of the skinor the hair.